Assessment, Therapy and Prevention Of Autoimmune Disease

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

We are now focusing on the idiopathic inflammatory myopathies (IIM), also known as the myositis syndromes, as prototypic autoimmune diseases from which principles learned in these disorders may be applied generally to other diseases. The myositis syndromes are associated with substantial lifelong morbidity and mortality. Their treatment is unsatisfactory in many cases and drug efficacy evaluation is hampered by the lack of reliable and standardized measures of disease outcome. Few therapies have been studied in randomized controlled clinical trials. Because of the lack of consensus on how to best measure disease in the myositis syndromes, and to enhance recruitment of patients for other studies, new disease assessment tools are being developed and validated to apply to all forms of myositis in both adults and children. We have organized a multidisciplinary collaborative group of over 450 adult and pediatric specialists with special interest in myositis, known as the International Myositis Assessment and Clinical Studies Group (IMACS) to assist in this project. The goals of IMACS are to standardize the conduct and reporting of clinical studies in all forms of IIM. Achieving these goals should enhance the consistency by which clinical trials are performed, improve the capacity to compare different treatments, and encourage development of promising novel therapeutic agents. Therapeutic studies of novel biologic agents are in progress and others are being planned to utilize these outcome measures in prospective trials. Together, and with input from the FDA and the European regulatory bodies, and with collaboration with Pediatric Rheumatology International Trials Organization (PRINTO), IMACS has: 1) developed and validated new tools to assess myositis disease activity and damage; 2) achieved consensus on core set outcome measures to comprehensively assess disease activity; 3) delineated preliminary definitions of improvement for use as clinical trial outcomes, which provide clinically meaningful change in combinations of the core set measures in a composite endpoint; 4) developed international consensus guidelines on details of the conduct of multi-center therapeutic trials for adult and juvenile IIM; 5) developed a clinical trial and outcomes data repository to allow us to reassess and revise IMACS tools; 6) developed new ACR-EULAR approved response criteria for polymyositis and dermatomyositis in adults and children that should result in more sensitive evaluations and fewer subjects needed for future clinical trials; and 7) in collaboration with other myositis researchers and consortia, have defined new classification criteria for adult and juvenile myositis which are provisionally approved by EULAR-ACR and should result in broader agreement on the inclusion of subjects in future clinical studies and trials. We have created a website to consolidate all IMACS activities, member lists, educational materials, presentations, references, assessment tools, and ongoing collaborative initiatives and studies (https://www.niehs.nih.gov/research/resources/imacs/index.cfm). To develop response criteria for juvenile dermatomyositis (DM) and adult DM and polymyositis (PM), we analyzed the performance of more than 300 candidate response criteria that used core set activity measures from either the IMACS or PRINTO and were derived from natural history data and a conjoint analysis survey. These were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis trial. At a consensus conference, myositis experts considered top candidate criteria based on their performance characteristics and clinical face validity. Consensus was reached for a conjoint analysis-based continuous model, using absolute per cent change in core set measures to determine minimal, moderate, and major improvement. The same criteria were chosen for adult DM and PM, with differing thresholds for improvement. These new response criteria had excellent performance characteristics in existing datasets and should be sensitive criteria that will provide a uniform approach for assessing treatment responses in future therapeutic and preventive clinical trials. These criteria are now approved by the American College of Rheumatology and European League Against Rheumatism. The growing differences among specialties in terms of how the idiopathic inflammatory myopathies (IIM) and their major subgroups are defined is leading to difficulties in conducting multispecialty international clinical trials and in comparing new findings from multiple basic and clinical research studies. To address this, candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide based on data from 976 IIM patients and 624 non-IIM patients with mimicking conditions. New classification criteria for IIM with readily assessable measurements and symptoms have been developed that generally show superior performance compared with existing criteria. These criteria use a model system with differential weights for the clinical and laboratory variables, and then a classification tree approach to the sub-classification of clinical subgroups of myositis. These criteria have been accepted by the American College of Rheumatology- European League Against Rheumatism and have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and enable classification of definite, probable, and possible IIM, in addition to the major subgroups of IIM. These new classification criteria had excellent performance characteristics and should be sensitive criteria that will provide a uniform approach for assessing in future clinical studies of IIM patients. These criteria are now provisionally approved by the American College of Rheumatology and European League Against Rheumatism. The therapy of myositis is focused on immunosuppression to minimize effects from immune activation and rehabilitation to improve remaining muscle function. Given the poor outcomes of myositis patients with standard therapy, novel biologic anti-inflammatory agents, which have been shown to be safe and effective for other immune-mediated diseases and have rationale for use in myositis, are reasonable candidates for study and may represent important advances in the treatment of myositis in the future. Our experience is that conducting therapeutic trials also greatly enhances recruitment to our epidemiologic investigations. We have taken advantage of the rituximab in myositis trial to identify changes in gene expression patterns in muscle and peripheral blood and the imaging features and immunopathology of muscle before (week 0) and after (week 16) therapy. Myeloid type I IFN signature genes were expressed at higher levels at baseline in the skeletal muscle of rituximab responders than in non-responders, whereas classic non-myeloid IFN signature genes were expressed at higher levels in non-responders at baseline. Also, rituximab responders had a greater reduction of the myeloid and non-myeloid type I IFN signatures than non-responders. These findings suggest that high levels of myeloid type I IFN gene expression in skeletal muscle predict responses to rituximab in PM/DM and that rituximab responders also have a greater decrease in the expression of these genes. We are currently evaluating treatment responses and factors associated with these for sodium thiosulfate as a novel therapy for moderate to severe calcinosis, and collaborating with investigators in NIAMS on treatment responses of JAK kinase inhibitors in patients with dermatomyo